This invention relates generally to materials which are resistant to in vivo calcification, and more particularly, to calcification-resistant biomaterial implants comprising synthetic polymers or materials of natural origin, such as bovine pericardium, porcine heart valves or homografts, incorporated with multivalent metallic cations as anticalcification agents.
The life expectancy of patients with severe cardiac valve disease is limited. Valve replacement surgery is often the only means of treating the problem. However, at the present time, there are no replacements for diseased heart valves which are totally problem-free. Currently used replacement valves include mechanical valves which may be composed entirely of a synthetic polymeric material such as polyurethane; bioprosthetic valves derived from glutaraldehyde-pretreated bovine pericardium or porcine aortic valves; and aortic homografts.
Use of mechanical valves is frequently complicated by thrombosis and tissue overgrowth leading to valvular failure. Calcification, however, has emerged as the most frequent cause of the clinical failure of bioprosthetic heart valves fabricated from porcine aortic valves or bovine pericardium. Human aortic homograft implants have also been observed to undergo pathologic calcification involving both the valvular tissue as well as the adjacent aortic wall albeit at a slower rate than the bioprosthetic heart valves. Pathologic calcification leading to valvular failure, in such forms as stenosis and/or regurgitation, necessitates re-implantation. Therefore, the use of bioprosthetic heart valves and homografts has been limited because such tissue is subject to calcification. Pathologic calcification also complicates the use of synthetic vascular grafts and other artificial heart devices, such as pacemakers, because it effects the flexibility of the synthetic polymers used to produce the synthetic devices.
Bioprosthetic heart valves from glutaraldehyde-pretreated bovine pericardium or porcine aortic valves provide blood flow characteristics which closely approximate the natural physiologic. Moreover, use of bioprostheses is accompanied by low incidence of thrombosis, and hence, does not require the administration of anticoagulants. Thus, bioprostheses are the replacement valves of choice, particularly for active children and adolescents. Unfortunately, while calcification of bioprostheses has caused valve failure in patients of all ages, there is a greater incidence of such valve failure in children and young adults. Over 50% of all reported valve implants placed in children under the age of 15 years at the time of initial implantation result in bioprosthesis failure due to calcification within 5 years. In comparison, porcine aortic valve bioprostheses implanted in adults have about a 20% incidence of failure due to calcification after 10 years of implantation. Efforts to provide long term inhibition of calcification have been unsuccessful to date. Currently, the problem of calcification-induced valve failure has prevented the widespread use of bioprosthetic heart valves, even in those patients who could benefit significantly therefrom.
Research on the inhibition of calcification of bioprosthetic tissue has focused on tissue pretreatment with either detergents or diphosphonates. Both of the aforementioned compounds tend to wash out of the bioprosthetic tissue with time due to blood-material interactions. Thus, these treatments merely delay the onset of the inevitable calcification process. To date, long-term prevention of calcification has been an unattainable result. Accordingly, there is a need for a long-term anticalcification agent for incorporation into bioprosthetic heart valves and other implantable, or in-dwelling, devices which are subject to in vivo pathologic calcification.
The mechanism for pathological calcification of cardiovascular tissue is not understood. Generally, the term "pathologic calcification" refers to the deposition of calcium phosphate mineral salts in association with a disease process. Calcification may be due to host factors, implant factors, and extraneous factors such as mechanical stress. There is some evidence to suggest that deposits of calcium are related to devitalized cells, especially membrane cells, where the calcium pump (Ca.sup.+2 -Mg.sup.+2 -ATPase) responsible for maintaining low intracellular calcium levels is no longer functioning. Calcification has been observed to begin with an accumulation of calcium and phosphorous, present as hydroxyapatite, which develops into nodules which can eventually lead to valvular failure.
We have discovered that the presence of certain multivalent metallic cations, such as trivalent aluminum or ferric cations, prevent in vivo calcification of biomaterials. There are no known examples in the prior art of the use of aluminum or iron salts to inhibit calcification of biomaterials.
Although aluminum is one of the most abundant elements occurring in nature, it plays no biologic role in human physiology. Aluminum has been used for medicinal purposes for many years and can be found in antacids, antiperspirants, acne medications, antidiarrheals, and products used to treat insect bites and stings. Such aluminum-containing products show no toxicity when applied topically; however, high doses of antacids have been known to cause metabolic disturbances, including gastrointestinal absorption of aluminum. Aluminum toxicity, including severe dementia and osteomalacia, has been observed in patients receiving long term hemodialysis. Osteomalacia has been found to correlate with ineffective calcium phosphate mineral deposition in the bones and an increased level of Al.sup.+3 in the bones. Additionally, the trivalent cation of aluminum (Al.sup.+3), found in trace amounts in intravenous fluid preparations, has been associated with altered bone mineralization and osteomalacia in patients, such as premature infants, receiving intravenous therapy.
Iron, of course, plays an essential role in biological processes. Iron is found in hemoglobin, the oxygen-carrying molecule of red blood cells in vertebrates, and myoglobin, a hemoglobin-like protein pigment occurring in muscles, for example. Therefore, iron is relatively non-toxic to humans.
It is therefore an object of the invention to provide biomaterials for implantation in a human or animal body which have increased resistance to in vivo pathologic calcification.
It is another object of the invention to provide biomaterials for implantation in a human or animal body which have a long-term, or prolonged, resistance to pathologic calcification.
It is further object of the invention to provide biomaterials for implantation in a human or animal body which exhibit localized calcification inhibition due to anticalcification agents incorporated therein, and thereby avoid the toxic side effects of the anticalcification agents, such as trivalent aluminum, which can result in growth retardation and calcium imbalance from the dosage level required for systemic administration.
It is yet another object of the invention to provide a method of fabricating and/or treating biomaterials for implantation in a human or animal body to render the biomaterials resistant to in vivo pathologic calcification.
It is still a further object of the invention to provide a method of treating tissues of natural origin, such as bioprosthetic heart valves fabricated from bovine pericardium or porcine aortic leaflets, and aortic homografts, which have long-term resistance to pathologic calcification and a reduced risk of valvular failure.
It is yet a further object of the invention to provide a method of making a synthetic organic polymer, such as polyester, polytetrafluoroethylene, polyurethane, nylon or silastic or other silicone-based material, having an anticalcification agent incorporated therein.